CN107501237A - A kind of Apalutamide new synthetic method - Google Patents
A kind of Apalutamide new synthetic method Download PDFInfo
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- CN107501237A CN107501237A CN201710755384.1A CN201710755384A CN107501237A CN 107501237 A CN107501237 A CN 107501237A CN 201710755384 A CN201710755384 A CN 201710755384A CN 107501237 A CN107501237 A CN 107501237A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of Apalutamide new synthetic method, first, react to obtain 4 (1 carboxyl ring fourth amino) 2 fluorine N methyl benzamides using 1 amino ring fourth formic acid and the fluorine N methyl benzamides of 4 bromine 2, then it is reacted with the cyanopyridine of 5 amino, 3 trifluoromethyl 2 and thio phosgene and this product is made, in whole production process, Cymag or potassium cyanide raw material need not be used, avoids security incident caused by above-mentioned toxic raw materials；1 amino ring fourth formic acid property is stable simultaneously, is easier to refine compared with cyclobutanone technique, the finished product other impurities of synthesis are less；This method can make cost reduce by more than 35%, so as to be advantageous to marketing and benefit vast sufferer.
Description
Technical field
The present invention relates to field of medicaments, specifically a kind of Apalutamide new synthetic method.
Background technology
Prostate cancer is the most common malignant tumour of male reproductive system, falls ill with the age and increases, be only second to lung cancer, is
The second of male cancer deaths.The method of traditional treatment prostate cancer is such as than card by operation or male sex hormone antagonist
Shandong amine (Bicalutamide), abiraterone or the miscellaneous Shandong amine of grace etc. are treated, but patient can produce anti-medicine after 2-4
Property, and the not application listing at home of the miscellaneous Shandong amine of grace, by clinical trial, it is found that Apalutamide is effectively to substitute
Medicine.The original synthetic routes of Apalutamide see WO2008119015, US20110003839, US20100190991,
The documents such as the A1 of US20130116258, WO 2014190895, specific synthetic route is as shown in figure 1, wherein mesosome TMSCN is produced
Process uses substantial amounts of Cymag or potassium cyanide, the harmful effects such as poisoning can be caused to operator, and caused waste water has
Pollute the potential risk of environment.The initial feed cyclobutanone that the other route uses is restricted by process safety, is commercially produced and is deposited
In difficulty, downstream product is caused to hold at high price.
The content of the invention
It is an object of the present invention to provide a kind of Apalutamide new synthetic method, to solve to lack present in prior art
Fall into..
The technical scheme that the present invention solves above-mentioned technical problem is as follows：
A kind of Apalutamide new synthetic method, comprises the following steps：
1) the fluoro- N-methyl-benzamides of the bromo- 2- of 4-, 1- amino ring fourths formic acid, acid binding agent, 2- are separately added into reactor
Acetyl cyclohexanone, water and DMF, after stirring and dissolving under inert gas shielding, cuprous iodide is added, 100-120 is heated to and takes the photograph
Family name's degree, after reacting 12-36 hours, cooling adds water and adds ethyl acetate extraction；
2) retain aqueous phase, be equal to 3 using salt acid for adjusting pH value, filter the solid of precipitation, be beaten with water, obtain 4- (1- carboxylics
Base-ring fourth amino) the fluoro- N- methyl-benzamides of -2- are standby；
3) thio phosgene is added drop-wise to 4- (1- carboxyls-ring fourth amino) the fluoro- N- methyl-benzamides of -2- and 5- amino -3-
In the dimethyl acetamide 500ml solution of trifluoromethyl -2- cyanopyridines, after being heated to 65 degree, 12 hours, methanol is added
500ml, water 500ml and concentrated hydrochloric acid 200ml are heated to reflux 2h；
4) solution in step 3) is added into ethyl acetate extraction, and after washed with brine, anhydrous sodium sulfate drying concentration
Yellow-brown solid is obtained, product Apalutamide is recrystallized to give with ethyl acetate and petroleum ether.
Wherein, above-mentioned steps 1) in reactor volume be 200L, the fluoro- N-methyl-benzamides of the bromo- 2- of 4- are 12.0kg,
51.7mole；1- amino ring fourth formic acid is 6.3kg, 61.7mole；Acid binding agent is 16.5kg, 155mole potassium carbonate；2- acetyl
Pentylcyclohexanone is 0.12kg, 1.05mole, water 1.2L；DMF is 70L；Cooling plus water are 120L；
Wherein, salt acid normality is 1N in step 2)；
Wherein, the thio phosgene in step 3) is 32g, 0.26mole；4- (1- carboxyls-ring fourth amino) fluoro- N- first of -2-
Base-benzamide is 80g, 0.26mole；5- amino -3- trifluoromethyl -2- cyanopyridines are 50g, 0.26mole；
Wherein, the solvent ratios that crystallization uses in step 4) are ethyl acetate: petroleum ether=1: 3~1: 5；
The method advantage that the invention is provided is：In whole production process, it is not necessary to using Cymag or potassium cyanide raw material,
Security incident caused by avoiding above-mentioned toxic raw materials；1- amino ring fourth formic acid property is stable simultaneously, is easier compared with cyclobutanone technique
Refined, the finished product other impurities of synthesis are less；This method can make cost reduce by more than 35%, so as to be advantageous to marketing and
Benefit vast sufferer.
Brief description of the drawings
Fig. 1 is existing Apalutamide synthetic route chart；
Fig. 2 is the synthetic route chart shown in Apalutamide new synthetic method；
Embodiment
With reference to embodiment, the present invention is described in detail.
A kind of Apalutamide new synthetic method, comprises the following steps：
1) the fluoro- N-methyl-benzamides of the bromo- 2- of 4-, 1- amino ring fourths formic acid, acid binding agent, 2- are separately added into reactor
Acetyl cyclohexanone, water and DMF, after stirring and dissolving under inert gas shielding, cuprous iodide is added, 100-120 is heated to and takes the photograph
Family name's degree, after reacting 12-36 hours, cooling adds water and adds ethyl acetate extraction；
2) retain aqueous phase, be equal to 3 using salt acid for adjusting pH value, filter the solid of precipitation, be beaten with water, obtain 4- (1- carboxylics
Base-ring fourth amino) the fluoro- N- methyl-benzamides of -2- are standby；
3) thio phosgene is added drop-wise to 4- (1- carboxyls-ring fourth amino) the fluoro- N- methyl-benzamides of -2- and 5- amino -3-
In the dimethyl acetamide 500ml solution of trifluoromethyl -2- cyanopyridines, after being heated to 65 degree, 12 hours, methanol is added
500ml, water 500ml and concentrated hydrochloric acid 200ml are heated to reflux 2h；
4) solution in step 3) is added into ethyl acetate extraction, and after washed with brine, anhydrous sodium sulfate drying concentration
Yellow-brown solid is obtained, product Apalutamide is recrystallized to give with ethyl acetate and petroleum ether.
Wherein, above-mentioned steps 1) in reactor volume be 200L, the fluoro- N-methyl-benzamides of the bromo- 2- of 4- are 12.0kg,
51.7mole；1- amino ring fourth formic acid is 6.3kg, 61.7mole；Acid binding agent is 16.5kg, 155mole potassium carbonate；2- acetyl
Pentylcyclohexanone is 0.12kg, 1.05mole, water 1.2L；DMF is 70L；Cooling plus water are 120L；
Wherein, salt acid normality is 1N in step 2)；
Wherein, the thio phosgene in step 3) is 32g, 0.26mole；4- (1- carboxyls-ring fourth amino) fluoro- N- first of -2-
Base-benzamide is 80g, 0.26mole；5- amino -3- trifluoromethyl -2- cyanopyridines are 50g, 0.26mole；
Wherein, the solvent ratios that crystallization uses in step 4) are ethyl acetate: petroleum ether=1: 3~1: 5；
Example is reacted, referring to Fig. 2,1- amino ring fourth formic acid, after N-methyl-benzamide fluoro- with the bromo- 2- of 4- reaction,
Reacted with 5- amino -3- trifluoromethyl -2- cyanopyridines, then by with after thiophosgene ring closure reaction, obtaining finished product
Apalutamide.Its detailed process is as follows：
The first step：The synthesis of the fluoro- N- methyl-benzamides (intermediate 2) of 4- (1- carboxyls-ring fourth amino) -2-：200
Rise and the fluoro- N-methyl-benzamides of the bromo- 2- of 4- (12.0kg, 51.7mole) are added in reactor, 1- amino ring fourths formic acid (6.3kg,
61.7mole), potassium carbonate (16.5kg, 155mole), 2- acetyl cyclohexanone (0.12kg, 1.05mole), 1.2 liters of water, are dissolved in
During DMF70 rises, stir and add CuI (0.2kg, 1.05mol) under lower nitrogen protection, be heated to 110 degree, react 24 hours.Reaction
After, 120 liters of cooling plus water, add ethyl acetate extraction.
Retain aqueous phase, adjust PH=3 with 1N hydrochloric acid, filter the solid of precipitation.It is beaten with water, obtains 11.8 kilograms of sterling,
Product 86%.HPLC：99.2%MS：266.32M+H.NMR in DMSO confirm.
Second step：4- [7- (6- cyano group -5- trifluoromethyl -3- pyridine radicals) -8- oxos -6- is thio -5,7- diaza spiros
The synthesis of the fluoro- N- methyl-benzoyls (compound 4) of [3,4] -5- octyl groups -2-：Thio phosgene (32g, 0.26mole) is added drop-wise to
The dimethylacetamide of intermediate 2 (80g, 0.26mole) and 5- amino -3- trifluoromethyl -2- cyanopyridines (50g, 0.26mole)
In amine 500ml solution, 65 degree are heated to, adds methanol 500ml, water 500ml and concentrated hydrochloric acid 200ml and is heated to reflux 2h overnight.Second
Acetoacetic ester extracts, salt water washing, anhydrous sodium sulfate drying, concentration.Obtain yellow-brown solid.Tied again with ethyl acetate/petroleum ether
Crystalline substance obtains product 55.6g, yield 43.8%.
H-NMR (CD3OD, 400MHz)：9.18 (1H, d, J=2.0Hz), 8.66 (1H, d, J-2.0Hz), 7.95 (1H,
M), 7.42 (2H, m), 2.99 (3H, s), 2.73 (2H, m), 2.60 (2H, m), 2.16 (1H, m), 1.67 (1H, m) .MS 478.1
(M+H)。
The method advantage that the invention is provided is：
1st, successfully avoid using Cymag or potassium cyanide as raw material, what need to be reacted in reaction under the conditions of acetic acid lacks
Fall into, avoid the problem of hydrogen cyanide is easily caused security incident in production；
2nd, 1- amino ring fourth formic acid property is stable, and refined, the finished product other impurities of synthesis are easier compared with cyclobutanone technique
It is less.
3rd, other raw materials that the route uses are market conventional products, can be reduced former route cost using the route
More than 35%, so as to be advantageous to marketing and benefit vast sufferer.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc., it should be included in the scope of the protection.
Claims (5)
- A kind of 1. Apalutamide new synthetic method, it is characterised in that：Comprise the following steps：1) the fluoro- N-methyl-benzamides of the bromo- 2- of 4-, 1- amino ring fourths formic acid, acid binding agent, 2- acetyl are separately added into reactor Pentylcyclohexanone, water and DMF, after stirring and dissolving under inert gas shielding, cuprous iodide is added, is heated to 100-120 degrees Celsius, After reacting 12-36 hours, cooling adds water and adds ethyl acetate extraction；2) retain aqueous phase, be equal to 3 using salt acid for adjusting pH value, filter the solid of precipitation, be beaten with water, obtain 4- (1- carboxyls-ring Fourth amino) the fluoro- N- methyl-benzamides of -2- are standby；3) thio phosgene is added drop-wise to 4- (1- carboxyls-ring fourth amino) the fluoro- N- methyl-benzamides of -2- and 5- amino -3- trifluoros In the dimethyl acetamide 500ml solution of methyl -2- cyanopyridines, after being heated to 65 degree, 12 hours, methanol 500ml, water are added 500ml and concentrated hydrochloric acid 200ml are heated to reflux 2h；4) solution in step 3) is added into ethyl acetate extraction, and obtained after washed with brine, anhydrous sodium sulfate drying concentration Yellow-brown solid, product Apalutamide is recrystallized to give with ethyl acetate and petroleum ether.
- 2. Apalutamide according to claim 1 new synthetic method, it is characterised in that：Reactor holds in step 1) Product is 200L, and the fluoro- N-methyl-benzamides of the bromo- 2- of 4- are 12.0kg, 51.7mole；1- amino ring fourth formic acid is 6.3kg, 61.7mole；Acid binding agent is 16.5kg, 155mole potassium carbonate；2- acetyl cyclohexanones are 0.12kg, and 1.05mole, water are 1.2L；DMF is 70L；Cooling plus water are 120L.
- 3. Apalutamide according to claim 1 new synthetic method, it is characterised in that：Salt acid equivalent in step 2) Concentration is 1N.
- A kind of 4. Apalutamide according to claim 2 new synthetic method, it is characterised in that：Sulphur in step 3) It is 32g, 0.26mole for phosgene；4- (1- carboxyls-ring fourth amino) fluoro- N- methyl-benzamides of -2- are 80g, 0.26mole； 5- amino -3- trifluoromethyl -2- cyanopyridines are 50g, 0.26mole.
- A kind of 5. Apalutamide according to claim 2 new synthetic method, it is characterised in that：Crystallized in step 4) The solvent ratios used are ethyl acetate: petroleum ether=1: 3~1: 5.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047200A (en) * | 2017-12-05 | 2018-05-18 | 上海丰瑞医药科技有限公司 | A kind of Preparation Method And Their Intermediate of diaryl thiohydantoin class compound |
| CN108311155A (en) * | 2018-05-14 | 2018-07-24 | 邢月军 | A method of catalysis prepares treatment prostate cancer disease drug A Palu amine intermediates |
| WO2018136001A1 (en) * | 2017-01-18 | 2018-07-26 | Scinopharm Taiwan, Ltd. | Process for preparing apalutamide |
| CN108383749A (en) * | 2018-01-30 | 2018-08-10 | 杭州科巢生物科技有限公司 | The synthetic method and its intermediate of A Palu amine |
| CN109988077A (en) * | 2017-12-29 | 2019-07-09 | 上海法默生物科技有限公司 | A kind of synthetic method and intermediate of A Palu amine |
| CN110511206A (en) * | 2019-06-17 | 2019-11-29 | 扬子江药业集团江苏海慈生物药业有限公司 | Aryl -2- thiohydantoin class compound intermediate, preparation method and application |
| US10513504B2 (en) | 2018-03-08 | 2019-12-24 | Apotex Inc. | Processes for the preparation of apalutamide and intermediates thereof |
| CN112218856A (en) * | 2018-05-30 | 2021-01-12 | 欧伦股份公司 | Process for preparing apaluramine |
| CN113292535A (en) * | 2021-06-18 | 2021-08-24 | 南京方生和医药科技有限公司 | Method for preparing apaluamide intermediate and apaluamide |
| CN113402466A (en) * | 2021-06-18 | 2021-09-17 | 南京方生和医药科技有限公司 | Apaglucone intermediate and method for preparing apalone |
| CN115536634A (en) * | 2022-10-17 | 2022-12-30 | 上海博悦生物科技有限公司 | Synthetic method of apatamide |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018136001A1 (en) * | 2017-01-18 | 2018-07-26 | Scinopharm Taiwan, Ltd. | Process for preparing apalutamide |
| CN108047200A (en) * | 2017-12-05 | 2018-05-18 | 上海丰瑞医药科技有限公司 | A kind of Preparation Method And Their Intermediate of diaryl thiohydantoin class compound |
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| US10513504B2 (en) | 2018-03-08 | 2019-12-24 | Apotex Inc. | Processes for the preparation of apalutamide and intermediates thereof |
| CN108311155A (en) * | 2018-05-14 | 2018-07-24 | 邢月军 | A method of catalysis prepares treatment prostate cancer disease drug A Palu amine intermediates |
| CN108311155B (en) * | 2018-05-14 | 2020-11-06 | 上海奥萝拉医药科技有限公司 | Method for catalytically preparing apalumide intermediate serving as medicine for treating prostate cancer |
| CN112218856A (en) * | 2018-05-30 | 2021-01-12 | 欧伦股份公司 | Process for preparing apaluramine |
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| CN110511206A (en) * | 2019-06-17 | 2019-11-29 | 扬子江药业集团江苏海慈生物药业有限公司 | Aryl -2- thiohydantoin class compound intermediate, preparation method and application |
| CN113292535A (en) * | 2021-06-18 | 2021-08-24 | 南京方生和医药科技有限公司 | Method for preparing apaluamide intermediate and apaluamide |
| CN113402466A (en) * | 2021-06-18 | 2021-09-17 | 南京方生和医药科技有限公司 | Apaglucone intermediate and method for preparing apalone |
| CN113292535B (en) * | 2021-06-18 | 2022-07-01 | 南京方生和医药科技有限公司 | Method for preparing apaluamide intermediate and apaluamide |
| CN115536634A (en) * | 2022-10-17 | 2022-12-30 | 上海博悦生物科技有限公司 | Synthetic method of apatamide |
| CN115536634B (en) * | 2022-10-17 | 2024-06-11 | 上海博悦生物科技有限公司 | Synthesis method of apatamide |
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